The Combination of Binding Avidity of Ovomucoid-Specific IgE Antibody and Specific IgG4 Antibody Can Predict Positive Outcomes of Oral Food Challenges during Stepwise Slow Oral Immunotherapy in Children with Hen's Egg Allergy.

To increase the prediction accuracy of positive oral food challenge (OFC) outcomes during stepwise slow oral immunotherapy (SS-OIT) in children with a hen's egg (HE) allergy, we evaluated the predictive value of the combination of antigen-specific IgE (sIgE) with antigen binding avidity and sIgG4 values. Sixty-three children with HE allergy undergoing SS-OIT were subjected to repeated OFCs with HE. We measured the ovomucoid (OVM)-sIgE by ImmunoCAP or densely carboxylated protein (DCP) microarray, sIgG4 by DCP microarray, and the binding avidity of OVM-sIgE defined as the level of 1/IC50 (nM) measured by competitive binding inhibition assays. The OFC was positive in 37 (59%) patients undergoing SS-OIT. Significant differences in DCP-OVM-sIgE, CAP-OVM-sIgE, I/IC50, DCP-OVM-sIgG4, the multiplication products of DCP-OVM-sIgE, and the binding avidity of DCP-OVM-sIgE (DCP-OVM-sIgE/IC50) and DCP-OVM-sIgE/sIgG4 were compared between the negative and positive groups (p < 0.01). Among them, the variable with the greatest area under the receiver operating characteristic curve was DCP-OVM-sIgE/IC50 (0.84), followed by DCP-OVM-sIgE/sIgG4 (0.81). DCP-OVM-sIgE/IC50 and DCP-OVM-sIgE/sIgG4 are potentially useful markers for the prediction of positive OFCs during HE-SS-OIT and may allow proper evaluation of the current allergic status in the healing process during HE-SS-OIT.

Author Correction: Oral immunotherapy combined with omalizumab for high-risk cow's milk allergy: a randomized controlled trial.

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper.

Dual Factors May Be Necessary for Development of Atopic March in Early Infancy.

The incidence of atopic diseases, including atopic dermatitis (AD), food allergies, allergic rhinitis, and asthma, has increased in recent decades, and currently affects approximately 20% of the population. Atopic march is the development of AD in infancy and subsequent food allergies, allergic rhinitis, and asthma in later childhood. Patients with infantile eczema may develop typical symptoms of AD, allergic rhinitis, and asthma at certain ages. Some patients' symptoms persist for several years, whereas others may have resolution with aging. Development of these diseases is strongly influenced by the following two factors: skin dysfunction caused by filaggrin mutations and development of colonization of microflora in early infancy. Filaggrin mutations predisposing to asthma, allergic rhinitis, and allergic sensitization, only in the presence of AD, strongly support the role of filaggrin in the pathogenesis of AD and in subsequent progression of the atopic march. Several studies have shown that development of colonization of microflora in early infancy might affect development of allergic disease or food desensitization. Therefore, massive allergen exposure to genetic skin dysfunction in early infancy and an imbalance of microflora might be necessary for development of atopic march.

Long-term safety of subcutaneous immunotherapy with TO-204 in Japanese patients with house dust mite-induced allergic rhinitis and allergic bronchial asthma: Multicenter, open label clinical trial.

BACKGROUND: To evaluate the long-term safety of subcutaneous immunotherapy with TO-204, a standardized house dust mite (HDM) allergen extracts, we conducted a multicenter, open label clinical trial. METHODS: Japanese patients aged 5-65 years were eligible for the study, if they had HDM-induced allergic rhinitis (AR), allergic bronchial asthma (BA), or both. TO-204 was administered in a dose titration scheme, and the maintenance dose was determined according to the predefined criteria. The treatment period was 52 weeks, and patients who were willing to continue the treatment received TO-204 beyond 52 weeks. This clinical trial is registered at the Japan Pharmaceutical Information Center (Japic CTI-121900). RESULTS: Between July 2012 and May 2015, 44 patients (28 with AR and 16 with allergic BA) were enrolled into the study. All patients were included in the analysis. The duration of treatment ranged from 23 to 142 weeks and the median maintenance dose was 200 Japanese allergy units (JAU). Adverse events occurred in 22 patients (50%). The most common adverse event was local reactions related to the injection sites. Four patients experienced anaphylactic reactions when they were treated with the dose of 500 JAU. Two patients experienced anaphylactic shock with the doses of 1000 JAU at onset. These 6 patients could continue the study with dose reduction. CONCLUSIONS: Safety profile of TO-204 was acceptable in Japanese patients with HDM-induced AR or allergic BA. Higher doses should be administered carefully, because the risk of anaphylaxis increased at doses of 500 or 1000 JAU.

Oral immunotherapy combined with omalizumab for high-risk cow's milk allergy: a randomized controlled trial.

We evaluated the efficacy and safety of oral immunotherapy (OIT) combined with 24 weeks of omalizumab (OMB) at inducing desensitization in children with cow's milk allergy (CM) compared with an untreated group. The present study was a prospective randomized controlled trial. Sixteen patients (age, 6-14 years) with high IgE levels to CM were enrolled in the present study. Patients were randomized 1:1 to receive OMB-OIT group or untreated group. The primary outcome was the induction of desensitization at 8 weeks after OMB was discontinued in OMB-OIT treated group and at 32 weeks after study entry. None of the 6 children in the untreated group developed desensitization to CM while all of the 10 children in the OIT-OMB treated group achieved desensitization (P < 0.001). A significantly decreased wheal diameter in response to a skin prick test using CM was found in the OMB-OIT treated group (P < 0.05). These data suggest that OIT combined with OMB using microwave heated CM may help to induce desensitization for children with high-risk CM allergy. This prospective randomized controlled trial was intended for 50 participants but was prematurely discontinued due to overwhelming superiority of OMB combined with microwave heated OIT over CM avoidance.

Immunotherapy for cow's milk allergy.

Oral immunotherapy (OIT) is used regularly for young children with cow's milk (CM) allergy and has been shown to be effective in several studies. However, adverse events occur frequently during OIT. Furthermore, there are only 5 randomized controlled trial studies of CM-OIT and these are low-powered single center trials. Therefore, evidence levels are also low and sometimes frequent and severe allergic events occur during the OIT. Furthermore, there are no standardized protocols in pediatric allergy guidelines from several countries and studies with long-term follow-up observations and clinical tolerance defined as sustained unresponsiveness are rare. Additionally, clinical tolerance by OIT is generally not well defined and obscure. Thus, several problems remain to be resolved, however we hope OIT in combination with omalizumab and less allergenic heated CM products will resolve these problems in the future.

Degradation and removal of soybean allergen in Japanese soy sauce.

Soy sauce is a traditional fermented seasoning of Japan and is available throughout the world. The two main raw ingredients of soy sauce are soybean and wheat, both of which are established food allergens. The present study examined the degradation and removal of soybean allergens in soy sauce by immunoblotting with anti­soybean protein antibody from rabbit and sera from two children with soybean allergy. It was demonstrated that soybean allergens were gradually degraded during the fermentation process, but were not completely degraded in raw soy sauce. During the processes of heat­treatment and filtration, the soluble soybean allergens in raw soy sauce were denatured to insoluble allergens by heat­treatment and subsequently completely removed from soy sauce by filtration. Therefore, to reduce the allergenicity of soy sauce, heat­treatment and filtration are very important processes in addition to the enzymatic degradation during the fermentation of soy sauce.

Erratum to: Two-weeks-sustained unresponsiveness by oral immunotherapy using microwave heated cow's milk for children with cow's milk allergy.

[This corrects the article DOI: 10.1186/s13223-016-0150-0.].

Two-weeks-sustained unresponsiveness by oral immunotherapy using microwave heated cow's milk for children with cow's milk allergy.

BACKGROUND: Several studies have reported that oral immunotherapy (OIT) is effective for children with cow's milk (CM) allergy. These studies reported the efficacy of OIT in terms of desensitization, but did not describe sustained unresponsiveness to CM. The aim of this study was to evaluate the efficacy of the OIT protocol using microwave heated cow's milk (MH-CM) in terms of 2-weeks-sustained unresponsiveness (2-weeks-SU) and safety. METHODS: Forty-eight children were enrolled in this study. Thirty-one children agreed to receive rush OIT using MH-CM (the OIT group) and another 17 children who did not want to receive rush OIT formed the untreated group. Rates of desensitization and 2-weeks-sustained unresponsiveness were compared between the two groups at 1 year after the start of OIT. We followed up these rates and safety data for another year and for longer in the OIT group. RESULTS: No children in the untreated group did not pass an open food challenge to CM. Of the 31 children in the OIT group, 14 (P = 0.002) achieved desensitization, and 8 (P = 0.036) achieved 2-weeks-SU to CM at 1 year from the start of OIT. Two years after the start of OIT, both the rate of desensitization and the rate of 2-weeks-SU in the OIT group significantly increased compared with the rates at 1 year (P = 0.025 and P = 0.008 respectively). CONCLUSIONS: The rush OIT protocol using MH-CM was effective at inducing 2-weeks-SU s to CM and had a good safety profile in children with CM allergy. Trial registration Approval number: 324, Registered 3 February 2009.

Successful desensitization in a boy with severe cow's milk allergy by a combination therapy using omalizumab and rush oral immunotherapy.

BACKGROUND: Rush oral immunotherapy (OIT) combined with omalizumab (OMB) has been reported to be an effective and safe treatment for severe milk allergies. However, no report has described long-term follow-up observations after OMB discontinuation. The purpose of this case report was to evaluate the safety and efficacy of rush OIT in combination with OMB during a long period of treatment. CASE PRESENTATION: A 5-year-old boy presented with a past history of two severe episodes of anaphylaxis (at the age of 2 and 3 years) after consuming small amounts of cow's milk (CM). Before the OIT, the total immunoglobulin E (IgE) level was 654 IU/mL, and specific-IgE (sIgE) levels for CM, casein, and ß-lactoglobulin were 77.0 kUA/L, 86.2 kUA/L and 12.0 kUA/L, respectively. The skin prick test (SPT) for CM showed a wheal (diameter, 20 mm) and erythema (diameter, 50 mm). In the open food challenge, he reacted to a 0.2 mL ingestion of CM and presented with dyspnea and laryngospasms, and he was then administrated 150 mg OMB every 2 weeks for 8 weeks. In the 9th week, he was admitted to hospital for the rush phase of the OIT. Once he was able ingest a dose of 200 mL CM without having an adverse reaction, he was discharged and allowed to continue a daily dose of 200 mL CM at home. During this phase, the sIgE levels were elevated, but the end-point titration values from the SPT gradually decreased, and the SPT was negative after 1 year of OMB treatment. Five months after discontinuation of OMB, the daily CM ingestion was ceased for a 2-week period, followed by an oral food challenge (OFC) that was negative. The patient experienced only five mild adverse events during the course of rush OIT, even after the discontinuation of OMB and his quality of life improved dramatically afterwards. CONCLUSIONS: The combination therapy of rush OIT and OMB successfully maintained desensitization to CM in a boy with severe allergies. We propose that a negative SPT may be useful to guide discontinuation of OMB in such patients.

Home-based oral immunotherapy (OIT) with an intermittent loading protocol in children unlikely to outgrow egg allergy.

BACKGROUND: Home based oral immunotherapy (OIT) for food allergy has often been used for young children in Japan, the majority of whom are believed to outgrow the allergy by the school age, therefore the true efficacy of the therapy has been controversial. The aim of this study was to evaluate the efficacy and safety of a newly developed slow- type home-based oral immunotherapy (OIT) regimen in children with hen's egg (HE) allergy, who had low likelihood of outgrowing the allergy, with treatment involving only elimination diet. METHOD: We retrospectively reviewed the medical records of 43 children with egg allergy (30 males; median age 6) who fulfilled Burks et al.'s criteria of being unlikely to outgrow the allergy. Thirty children who agreed to start OIT were assigned to the treatment group, and 13 who did not want to participate immediately were assigned to the untreated group; the patients underwent an elimination diet for 1 year, during which they were monitored. The OIT regimen involved the intake of the maximum tolerated dose 2 to 3 times a week at home, with initial dose introduction followed by dose build-ups with medical supervision. We statistically evaluated the rate of children who changed their threshold up to 32 g of egg - defined as, oral tolerance induction- in both the groups for 1 year and in the OIT group for 2 years, as well as the rate of children who fulfilled Savage et al.'s criteria of clinical tolerance after reaching the abovementioned remission stage. RESULTS: The rate of children who achieved oral tolerance induction to 32 g of egg after 1 year in the OIT group (9/30) was significantly higher than that in the untreated group (0/13). The total rate within the OIT group was significantly increased from 9/30 at 1 year to 17/30 at two years without any severe adverse reaction; of the above 17 children, we followed 14 children, and noted that 11 of these were able to obtain clinical tolerance. CONCLUSION: The home-based OIT with an intermittent loading protocol was very safe and effective in children with a low likelihood of outgrowing egg allergy.

New efficacy of LTRAs (montelukast sodium): it possibly prevents food-induced abdominal symptoms during oral immunotherapy.

BACKGROUND: The aim of the study was to elucidate whether leukotriene receptor antagonists (LTRAs) can prevent severe allergic reactions, which occur during oral immunotherapy (OIT) in children with food allergies. FINDINGS: Five children with food allergies [3 allergic to hen's egg (HE), 1 to wheat, and one to cow's milk (CM); aged between 7 and 12 years; median, 8.5 years] who were started on LTRAs during OIT were retrospectively selected from among 63 children undergoing OIT. In the rush phase, after the administration of the initial dose which was set in open food challenge test, the subsequent doses were increased by approximately 1.2 times of the previous dose and were administered every 2 hours, 4 times a day. The target doses of hen's egg, wheat (udon noodle), and cow's milk in the rush phase were 50 g, 200 g, and 200 ml, respectively. The ingestion of the target dose was continued at home every day for at least a year in the maintained phase.Four participants experienced intractable abdominal pain during the rush phase; therefore, the loading dose was not increased in these children. However, the administration of LTRAs prevented their symptoms, resulting in the completion of the rush phase. One participant also experienced intractable abdominal pain during the maintenance phase. After receiving LTRAs, the target dose was able to tolerated. CONCLUSION: The findings from this retrospective study suggest that the administration of LTRAs is useful for the prevention of adverse allergic reactions such as abdominal pain during OIT.

MEFV Variants in Patients with PFAPA Syndrome in Japan.

BACKGROUND: The pathogenesis of PFAPA (periodic fever, aphthous stomatitis, pharyngitis, adenitis) syndrome is unknown as yet. In order to understand whether genes implicated in other auto-inflammatory diseases might be involved in the pathogenesis of PFAPA, all variants in the genes causing familial Mediterranean fever (FMF), tumor necrosis factor (TNF) receptor-associated periodic syndrome (TRAPS), and Hyper IgD syndrome were analyzed in children with PFAPA. PATIENTS AND METHODS: All variants in MEFV, TNFRSF1A, and MVK were analyzed in 20 patients with PFAPA. PFAPA were diagnosed by previous published criteria. The findings of all analyses in PFAPA patients were compared with those of unaffected normal subjects (n=62). RESULTS: In the 13 children of 20 with PFAPA, the heterozygous variants of MEFV (5 patients: E148Q-L110P, 2 patients: E148Q, 1 patient: E148Q-L110P/E148Q, 1 patient: E148Q-P369S-R408Q-E84K, 1 patient: E148Q-L110P-P369S-A408G, 1 patient: R202Q, 1 patient: P115R) were found. No variants belonging to TNFRSF1A or MVK were detected in children with PFAPA. The frequency of the E148Q-L110P variants in children with PFAPA was significantly higher than that observed in unaffected normal subjects (7/20 versus 8/62). The duration of the episodes of illness in PFAPA children with MEFV variants was shorter than that of patients without variants. CONCLUSION: Genes involved in the development and progression of MEFV may affect the incidence and the phenotype of PFAPA in children.

Steroid pulse therapy for children with intravenous immunoglobulin therapy-resistant Kawasaki disease: a prospective study.

Patients with Kawasaki disease (KD) who did not respond to the initial IVIG are known to have higher risk for developing coronary arterial lesions (CALs). Our aim is to clarify whether patients with initial IVIG resistant KD may benefit from methylprednisolone pulse therapy (MPT) in comparison with re- treatment of IVIG (2nd IVIG). A total of 237 patients (median age: 2 years 2 months; range 1 months-10 years) with KD were initially treated with IVIG (2 g/kg). Among them, 41 patients (22 %) were assessed as IVIG resistance: these patients were allocated to either group A receiving MPT (n = 14) or group B receiving the 2nd IVIG (n = 27). Patients with resistant to the additional therapy (MPT or 2nd IVIG) were received second IVIG (group A) or MPT (group B). Changes in leukocyte count, C-reactive protein and albumin before and after an additional therapy were significantly greater in group A than those in group B. However, the prevalence of CALs did not differ between the groups (36 % in group A and 26 % in group B, p > 0.05). There was no significant difference in the medical cost between the groups (median cost: 92,032 JPY in group A and 97,331 JPY in group B). MPT does not reduce the risk of development to CAL and does not seem to be beneficial as single agent therapy for IVIG resistant KD.

Increased production of nitric oxide by phagocytic stimulated neutrophils in patients with chronic granulomatous disease.

Chronic granulomatous disease (CGD) is an inherited disorder in which phagocytic leukocytes fail to generate superoxide (O(2)(-)) and antimicrobial oxidants. Patients with CGD develop recurrent and often life-threatening infections due to catalase-positive microorganisms. We attempted to measure the production of nitric oxide and reactive oxygen species in polymorphonuclear neutrophils (PMNs) from patients with CGD using a flow cytometry technique. Venous blood was obtained from 5 male patients with X-linked CGD and from 10 healthy volunteers. The nitric oxide production by PMNs after phagocytosis was measured using diaminofluorescein-2 diacetate, a fluorescent indicator of intracellular nitric oxide production. After erythrocytes were hypotonically lysed, the cell pellet was applied to a cytofluorometer. Although the production of hydrogen peroxide by PMNs from patients with CGD was almost absent, nitric oxide production was detected at nearly half the level as was seen in the PMNs from healthy volunteers (CGD vs. healthy volunteers=140.1±28.6 vs. 256.4±10.3, mean fluorescence intensity; P<0.01). In conclusion, we demonstrated that human PMNs produces nitric oxide after phagocytic stimulation. Also nitric oxide production after phagocytic stimulation by PMNs of patients with CGD is observed although its amount is lower than that observed on healthy control. Despite the fact that CGD patients cannot produce H(2)O(2) which is essential for intracellular bacteriocidal process after phagocytosis, our data suggested that the phylactic effect in PMNs induced by nitric oxide could be at least partially related to the survival of patients with CGD.

Predictive value of IgE/IgG4 antibody ratio in children with egg allergy.

BACKGROUND: The aim of this study was to investigate the role of specific IgG4 antibodies to hen's egg white and determine their utility as a marker for the outcome of oral challenge test in children sensitized to hen's egg METHODS: The hen's egg oral food challenge test was performed in 105 sensitized children without atopic dermatitis, and the titers of egg white-specific immunoglobulin G4 (IgG4) and immunoglobulin E (IgE) antibodies were measured. To set the cut-off values of IgG4, IgE, and the IgE/IgG4 ratio for predicting positive results in oral challenges, receiver operating characteristic curves were plotted and the area under the curves (AUC) were calculated. RESULTS: Sixty-four of 105 oral challenges with whole eggs were assessed as positive. The AUC for IgE, IgG4, and IgE/IgG4 for the prediction of positive results were 0.609, 0.724, and 0.847, respectively. Thus, the IgE/IgG4 ratio generated significantly higher specificity, sensitivity, positive predictive value (%), and negative predictive value (%) than the individual IgE and IgG4. The negative predictive value of the IgE/IgG4 ratio was 90% at a value of 1. CONCLUSIONS: We have demonstrated that the egg white-specific serum IgE/IgG4 ratio is important for predicting reactivity to egg during food challenges.

Diagnosis of autoimmune neutropenia by neutrophil-bound IgG and IgM antibodies.

Autoimmune neutropenia (AIN) in infancy is caused by antineutrophil (granulocyte-specific) autoantibodies. These antibodies are rarely found in circulation because their serum levels are extremely low. We hypothesized that a direct granulocyte immunofluorescence test (D-GIFT) that enables us to detect neutrophil-bound autoantibodies consisting of both immunoglobulin (Ig) G and IgM has better diagnostic value than the detection of circulating autoantibodies. Whole blood (100 µL) was obtained from 50 infants with AIN, 12 infants with transient neutropenia, and 37 control infants. D-GIFT was performed using both fluorescein isothiocyanate-conjugated antihuman IgG Fc portion monoclonal antibodies and fluorescein isothiocyanate antihuman IgM monoclonal antibodies. Results were assessed as relative fluorescence intensity (RFI). The RFIs of antineutrophil IgG-bound and antineutrophil IgM-bound cells in patients with AIN were significantly higher than those in patients with transient neutropenia and in controls. Positive results, as assessed by RFI scores of more than 1.81 in either antineutrophil IgG-bound or antineutrophil IgM-bound cells, showed the sensitivity and specificity of D-GIFT, and the areas under the receiver operating characteristic curve (0.98, 0.98, and 0.997, respectively) in the diagnosis of AIN. D-GIFT detecting both neutrophil-bound IgG autoantibodies and IgM autoantibodies has discriminatory power for identifying patients with AIN and, therefore, can be a useful diagnostic test.

Two types of orthostatic dysregulation assessed by diameter of inferior vena cava.

AIMS: Orthostatic dysregulation (OD) is common in adolescents. This study was conducted to evaluate the usefulness of the measurement of the diameter of the inferior vena cava (IVC) for objective assessment of patients with OD. METHODS: Twenty children with OD (median 14 years, range 9-15 years) and 23 age-matched healthy children (median 12 years, range 10-15 years) were enrolled. A diameter of IVC was measured by an abdominal echogram before and after a head-up tilt table testing (HUT). Changes in IVC was assessed by an arbitrary parameter, collapse index (CI) as the following equation: [(maximal IVC diameter in the supine position - maximal IVC diameter in the standing position)/(maximal IVC diameter in the supine position)]× 100. CI was evaluated 4 weeks after treatment with an adrenergic agent. RESULTS: Children with OD demonstrated either higher CI or lower CI compared to that in control children: CI was more than 50 (range 50-71) in 12 patients with OD while that was equal to or less than 0 (range -225 to 0) in eight out of 20 patients. In contrast, CI was between 0 and 50 (range 1-26) in 23 healthy children. Pharmacological treatment induced the normalization in the CI in both higher and lower CI group. CONCLUSION: OD can be classified into two subtypes: by HUT, one is characterized by an increase of IVC diameter while another is characterized by its decrease. Measurement of IVC diameter by HUT is useful to understand the pathophysiology and to assess the efficacy of treatment.